103 Metabolic Characterization of IDH1mutant and IDH Wildtype Gliomaspheres Uncovers Cell-type Specific Vulnerabilities

Abstract

Abstract INTRODUCTION Large scale sequencing of tumor banks has revealed a subset of tumors that have a mutation in the isocitrate dehydrogenase (IDH1) enzyme, which bestows a novel function of reducing alpha-ketoglutarate into 2-hydroxyglutarate (2-HG). There has been considerable interest in defining metabolic differences of IDH1mutant tumors to exploit in therapy. However, most studies are limited by over-expressing the mutant IDH1 gene on an IDH1WT background. In this study we attempt to define metabolic differences between a cohort of patient-derived IDH1mutant and IDH1WT gliomaspheres to design patient-specific therapy. METHODS We propagated 59 patient-derived gliomasphere lines (7 bearing IDH1mutations) and performed microarray expression and KEGG analysis to define the pathways that were differentially enriched in IDH1mutant and IDH1WT cells. We used mass spectroscopy with labeled glucose and glutamine to determine differences in metabolite uptake and utilization. We then used inhibitors of de novo synthesis and Xray radiation treatment to test the predictions made by our expression analysis. RESULTS >Expression analysis showed IDH1WT cells to be enriched for pathways involving de novo DNA synthesis while IDH1mutant cells were enriched for pathways involving DNA repair after radiation. Using LC-MS we were able to define labeling patterns between IDH1WT and IDH1mutant cells particularly in regards to glucose utilization in nucleotide precursors. IDH1WT cells utilize more of the de novo pathway to synthesize nucleotides and consequently to be more sensitive to inhibitors of de novo synthesis. IDH1mutant cells were found to show less DNA damage after radiation and to more quickly repair that damage. They also showed better growth after radiation. CONCLUSION In this study we have identified key metabolic differences between IDH1mutant and IDH1wildtype tumors that suggest these two groups require different treatment modalities.